Although coronary angioplasty opens the targeted stenotic lesion in over 95% of pts, restenosis develops in about 50% of pts. The factors predisposing to restenosis, however, are largely unknown. Analysis of atherectomy specimens of pts being treated for restenosis suggested that a virus might contribute to the development of restenosis. Specifically, we demonstrated that about one-third of the restenotic lesions contained CMV DNA, and that an immediate early (IE) gene product of CMV, IE84, bound to and inactivated the tumor suppressor protein p53. (This could predispose to SMC accumulation by increasing SMC proliferation and/or by inhibiting p53-mediated apoptosis.) This and other findings raised the possibility that CMV infection may predispose to restenosis, and that one of the mechanisms by which this could occur is by injury-induced reactivation of the latent virus leading to viral gene expression. In the first of a series of investigations designed to test this CMV-restenosis hypothesis further, we determined whether CMV increases injury-induced neointimal formation. We used the standard rat carotid injury model, and determined whether CMV infection altered the neointimal response to vascular injury. Left carotid balloon injury was performed on 30 male Spraque-Dawley rats. One day after injury, 15 received an intraperitoneal injection of approximately 10/6 active viral particles/ml of CMV, while another 15 rats received an intraperitoneal injection of normal saline. Assessment of the neointimal to medial (N/M) ratio revealed that the neointimal thickness of CMV infected animals was nearly 40% greater than that of controls. We conclude that CMV infection of immunocompetent adult rats increases the neointimal response to vascular injury. This finding further suggests that CMV may play a crucial role in the development of restenosis in pts undergoing angioplasty.